Circulation Research. 2001;88:1127-1134
Published online before print May 24, 2001, doi: 10.1161/hh1101.091339
Published online before print May 24, 2001, doi: 10.1161/hh1101.091339
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Recruitment of Serum Response Factor and Hyperacetylation of Histones at Smooth Muscle–Specific Regulatory Regions During Differentiation of a Novel P19-Derived In Vitro Smooth Muscle Differentiation System
From the Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Va.
Correspondence to Gary K. Owens, PhD, University of Virginia, Molecular Physiology and Biological Physics, PO Box 800736, Charlottesville, VA 22908-0736. E-mail gko{at}virginia.edu
Abstract
Abstract—Little
is known regarding transcriptional regulatory mechanisms that control
the sequential and coordinate expression of genes during smooth muscle
cell (SMC) differentiation. To facilitate mechanistic studies of SMC
differentiation, we established a novel P19-derived clonal cell line
(designated A404) harboring a smooth muscle (SM) 
-actin
promoter/intron-driven puromycin resistance gene. Retinoic acid plus
puromycin treatment stimulated rapid differentiation of multipotential
A404 cells into SMCs that expressed multiple SMC differentiation marker
genes, including the definitive SM-lineage marker SM myosin heavy
chain. Using this system, we demonstrated that various transcription
factors were upregulated coincidentally with the expression of SMC
differentiation marker genes. Of interest, the expression of serum
response factor (SRF), whose function is critical for SMC-specific
transcription, was high in undifferentiated A404 cells, and it did not
increase over the course of differentiation. However, chromatin
immunoprecipitation analyses showed that SRF did not bind the
target sites of endogenous SMC marker genes in chromatin in
undifferentiated cells, but it did in differentiated A404 cells, and it
was associated with hyperacetylation of histones H3 and H4.
The present studies define a novel cell system for studies of
transcriptional regulation during the early stages of SMC
differentiation, and using this system, we obtained evidence for the
involvement of chromatin remodeling and selective recruitment of SRF to
CArG elements in the induction of cell-selective marker genes during
SMC differentiation.
Key Words: smooth muscle • transcription • differentiation • serum response factor • chromatin remodeling
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